Mitochondrial quality is controlled by the selective removal of damaged mitochondria through mitophagy. Mitophagy impairment is associated with aging and many pathological conditions. An iron loss induced by iron chelator triggers mitophagy by a yet unknown mechanism. This type of mitophagy may have therapeutic potential, since iron chelators are clinically used. Here, we aimed to clarify the mechanisms by which iron loss induces mitophagy. Deferiprone, an iron chelator, treatment resulted in the increased expression of mitochondrial ferritin (FTMT) and the localization of FTMT precursor on the mitochondrial outer membrane. Specific protein 1 and its regulator hypoxia‐inducible factor 1α were necessary for deferiprone‐induced increase in FTMT. FTMT specifically interacted with nuclear receptor coactivator 4, an autophagic cargo receptor. Deferiprone‐induced mitophagy occurred selectively for depolarized mitochondria. Additionally, deferiprone suppressed the development of hepatocellular carcinoma (HCC) in mice by inducing mitophagy. Silencing FTMT abrogated deferiprone‐induced mitophagy and suppression of HCC. These results demonstrate the mechanisms by which iron loss induces mitophagy and provide a rationale for targeting mitophagic activation as a therapeutic strategy.

中文翻译：

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铁损失通过诱导线粒体铁蛋白触发线粒体自噬

线粒体质量是通过线粒体自噬选择性去除受损线粒体来控制的。Mitophagy 损害与衰老和许多病理状况有关。铁螯合剂引起的铁流失通过一种未知的机制触发线粒体自噬。这种类型的线粒体自噬可能具有治疗潜力，因为临床上使用铁螯合剂。在这里，我们旨在阐明铁损失诱导线粒体自噬的机制。去铁酮，一种铁螯合剂，治疗导致线粒体铁蛋白 (FTMT) 表达增加和 FTMT 前体在线粒体外膜上的定位。特定蛋白 1 及其调节剂缺氧诱导因子 1α 是去铁酮诱导的 FTMT 增加所必需的。FTMT 特异性地与核受体共激活因子 4（一种自噬货物受体）相互作用。去极化线粒体选择性地发生去铁酮诱导的线粒体自噬。此外，去铁酮通过诱导线粒体自噬抑制小鼠肝细胞癌 (HCC) 的发展。沉默 FTMT 消除了去铁酮诱导的线粒体自噬和 HCC 的抑制。这些结果证明了铁丢失诱导线粒体自噬的机制，并为靶向线粒体自噬作为治疗策略提供了依据。